Osteoarthritis (OA), which affects millions of Americans, is a debilitating condition characterized by the loss of articular cartilage at the join surfaces. Osteoarthritis is a promising candidate for regenerative stem cell therapy. However, despite decades of investigation, the cells and molecular pathways that repair cartilage remain undefined. Recently, we and another group (Irving Weissman's group at Stanford University), have independently identified a distinct population of skeletal stem cells in adult bone marrow. These cells live near the surfaces of the joints, are capable of self-renewal, and give rise to osteoblasts, cartilage cells (chondrocytes) and reticular cells during adulthood, and participate i the repair of fractures. The isolation of OCR cells raises a crucial question regarding the pathogenesis and treatment of OA. Do these cells contribute to tissue repair in OA? Could their function be augmented to assist in OA repair? In this proposal, we wish to investigate the origins of cartilage repair in vivo, test which mouse stem/progenitor populations repair cartilage, and define molecular pathways involved in cartilage repair. We will use a well-established model of OA in mice: transection of the medial menisco-tibial ligament, resulting in wear and tear degeneration of the articular cartilage that recapitulates the anatomical pathology of human osteoarthritis, including cartilage loss and bony sequelae, 4-8 weeks after injury. We wish to ask the following questions: What is the cellular origin of cartilage repair in OA? We will use lineage tracing from chondrocytes, OCR stem cells and MSCs in an OA model to determine the origin of cartilage repair. What are the best cells for repairing articular cartilage? We will assess if injecting these populations into the knee during OA reduces the cartilage damage. What are the targetable signaling pathways that promote OA repair? We will investigate and therapeutically utilize Bmp and VEGF signaling in cartilage differentiation and repair. We will define other signaling pathways relevant to chondrogenesis from OCR cells.